The eight subtypes of metabotropic glutamate receptors (mGluRs) belong to family C G protein-coupled receptors (GPCRs) and possess a large extracellular domain (ECD), seven transmembrane domains (TMD) and cytosolic C-terminal tail. The mGluRs are widely expressed in the central nervous system and play critical roles in regulating neuronal excitability and synaptic plasticity at both excitatory and inhibitory synapses (Neyman, S., et al. (2008) The European journal of neuroscience 27:1345-1352). Extensive structural studies have revealed that the endogenous agonist, L-Glutamate (L-Glu), the major excitatory neurotransmitter in the central nervous system, binds at the hinge region of the ECD within the receptor's Venus Fly Trap (VFT) motif to activate the protein. This subsequently stimulates phospholipase C (PLC) and leads to accumulation of inositol trisphosphate (IP3) and an increase of intracellular calcium concentration ([Ca2+]i) (Lavreysen, H., et al. (2003) Molecular pharmacology 63:1082-1093; Lindsley, C. W., et al. (2004) Journal of medicinal chemistry 47:5825-5828; Kubo, Y., et al. (1998) Science 279:1722-1725).
In recent years, mGluRs have received increasing interest as potential drug targets for the treatment of a range of psychiatric and neurological diseases (Whang, P. G., et al. (2008) Orthopedics 31(10)) (FIG. 1). The ligands targeting mGluRs can be classified as orthosteric agonists and antagonists as well as allosteric modulators. Orthosteric agonists and antagonists induce and attenuate, respectively, the activity of the receptor by competitively binding to the L-Glu binding pocket. L-Quisqualate (L-Quis), the most potent agonist of mGluR1 reported to date (Yuan, K., et al. (2011) J Biol Chem 286:24776-24784; Chen, Y., et al. (2011) The Biochemical journal 435:711-722), has been speculated to share nearly the same binding pocket as L-Glu (Levant, J. A., et al. (1973) The New England journal of medicine 289:555-558; Sato, T., et al. (2003) J Biol Chem 278:4314-4321). In contrast, (S)-α-Methyl-4-carboxyphenylglycine (“(s)-MCPG”) is an analog of L-Glu and a non-selective competitive antagonist that has been shown to occupy the L-Glu binding pocket, thereby blocking the function of group I/II members in the mGluR family (Tsuchiya, D., et al. (2002) Proc Natl Acad Sci USA. 99:2660-2665). On the other hand, allosteric modulators bind to sites other than the orthosteric center to affect the activity of the receptor. The molecule (9H-xanthene-9-carbonyl) carbamic acid butyl ester (“Ro 67-4853”) is a positive allosteric modulator (PAM) of mGluR1 that enhances the potency of L-Glu by interacting with the TMDs of the receptor. The molecule (−)-ethyl (7E)-7-hydroxyimino-1,7a-dihydrocyclopropa[b]chromene-1a-carboxylate (“CPCCOEt”) is a negative allosteric modulator (NAM) that inhibits the activation of mGluR1 by L-Glu by specifically binding to a site residing at the third extracellular loop of mGluR1α (Nagar, B., et al. (1996) Nature 380:360-364).